1. Field of the Invention
The present invention relates to novel intermediates useful in the synthesis of amlodipine and related compounds as well as to processes of making and using the same.
2. Description of the Related Arts
EP 89167 and corresponding U.S. Pat. No. 4,572,909 describe a class of dihydropyridine derivatives that exhibit antianginal and antihypertensive properties. One of the compounds disclosed therein has become a commercially important compound that is now known as amlodipine: or 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester, having the following formula: 
This compound, in the form of its besylate salt as described in EP 244 944 and in corresponding U.S. Pat. No. 4,879,303, is the active ingredient in the prescription pharmaceutical composition NORVASC sold by Pfizer Pharmaceuticals for management of hypertension and angina pectoris.
Generally, the synthetic route disclosed in EP 89167 for making amlodipine and the other related dihydropyridine compounds comprises forming the corresponding amino-group protected precursor followed by deprotection. Suitable protecting groups for the amino side chain group include benzylamino, dibenzylamino, azido and phthalimido groups. One of the precursors for amlodipine uses a phthalimido protecting group and is represented by the following formula (2a). 
This compound, which is hereinafter referred to as “phthalimidoamlodipine,” has certain advantages among other amino-protected precursors for amlodipine as it may be easily separated from the reaction mixture without danger (e.g. the azido-amlodipine is explosive) and is converted to amlodipine by simple, common deprotection procedures, e.g. by reaction with methylamine, hydrazine etc. It is thus considered to be a particularly useful key intermediate for industrial production of amlodipine.
J. Med. Chem. 1986, 29, 1696-1702 discloses two routes for making the phthalimidoamlodipine and other related amino-protected precursors. The first route comprises reacting a substituted benzaldehyde (A), such as 2-chlorobenzaldehyde, with methyl 3-aminocrotonate (B1) and amino protected aminoethoxy-methylacetoacetate (C1′). 
The compound (C1′) is prepared by a condensation of ethyl 2-chloroacetoacetate (shown hereinafter as compound (F)) with an appropriately substituted sodium alkoxide. Where —N(prot) represents a phthalimido-group, the alkoxide can be N-(2-hydroxyethyl)phthalimide (shown hereinafter as compound G).
The second route disclosed in this article, comprises reacting a benzylidene derivative (D1) (prepared in an extra step by an addition of a compound of formula (A), such as o-chlorobenzaldehyde, to methyl acetoacetate) with a substituted aminocrotonate (E1) (prepared in situ from the above amino-protected aminoethoxymethylacetoacetate (C1′) and ammonium acetate). 
This variant was also applied to the synthesis of phthalimidoamlodipine (2a) in WO 00-24714. Therein, the intermediating phthalimido-substituted aminocrotonate (E1) was not prepared in situ but was prepared and isolated in a solid state in an extra step prior to the reaction with the benzylidene compound.
The above methods suffer from yield and/or purity inefficiencies due to the reactivity of starting materials leading to formation of side products. For example, phthalimidoamlodipine is reported in the above-mentioned J. Med. Chem. Article as being prepared in 25% yield by following the first scheme (see compound 41 in Table I on page 1698). It would be desirable to provide a process for making phthalimidoamlodipine and related compounds in good yield and with good purity.